Monoclonal antibody (mAb) therapy is an important and growing part of medicine. Over 30 monoclonal antibodies have been approved for various immunological diseases, infectious diseases, and cancers either in the United States or Europe, and hundreds more are under investigation. However, a common problem in monoclonal antibody therapy development is lack of adequate efficacy despite Fab and FcR binding. Because of the high doses that are often necessary in order to achieve efficacy, adverse side effects are commonly associated with therapeutic antibodies. Further, low or altered expression of tumor and other target antigens, as well as genetic mutations that affect antibody targets or downstream effects of antibody binding, can render antibody therapies ineffective. As an example, the monoclonal antibody trastuzumab is a mAb directed specifically against the HER2/neu breast cancer antigen and commercially available under the trade name Herceptin®, is approved by the United States Food and Drug Administration for the treatment of breast cancer. Trastuzumab can be effective in patients in which HER2/neu is highly expressed; however, approximately 90% of breast cancer patients have tumors that are not classified as HER2/neu high expressing. As another example, cetuximab, a mAb directed specifically against the epidermal growth factor receptor (EGFR) and commercially available under the trade name Erbitux®, is approved by the United States Food and Drug Administration for the treatment of colon cancer. Cetuximab blocks the EGFR and arrests a downstream KRAS protein-dependent tumor proliferation pathway. From a clinical perspective, cetuximab can improve overall response rates as well as progression-free survival in patients whose tumors have wild type (WT) KRAS. Unfortunately, 30-60% of colon cancer patients have tumors with codon 12 or 13 KRAS mutations, and recent clinical trials suggest that patients with mutated KRAS do not benefit from treatment with cetuximab (summarized in Allegra et. al., Journal of Clinical Oncology, 2009 Apr. 20; 27(12):2091-6). Thus, there is a need for new antibody-like-based therapeutics in the treatment of cancers, as well as in the treatment of autoimmune disorders and inflammatory diseases.
Engagement and aggregation of Fc receptors, particularly low affinity receptors such as FcγRIIIa, on immune cells and especially on natural killer (NK) cells by antibodies results in activation, degranulation, and lysis of the target tumor or cell, in a process known as antibody dependent cellular cytoxicity (ADCC). Tumor cells and other cells targeted by the immune system may also be killed through complement-dependent cytoxicity (CDC), in which an antibody binds complement, leading to cell cytotoxicity; or through direct cytotoxicity (DC) resulting from direct antibody binding to antigen in the absence of NK cells or complement; or by other mechanisms such as induction of apoptosis, or interference with cellular growth or processes. There is presently a need in the art to identify means of increasing ADCC, CDC, DC, and other mechanisms of killing tumor cells or other cells, thereby increasing the efficacy of mAb therapies. In particular, when complement-dependent pathways for cell killing are fully functional, CDC can be an effective method for killing cancer cells and other target cells. However, many cells are resistant to CDC due to cell membrane repair mechanisms and regulatory proteins such as CD59, which inhibits the complement pathway. For example, despite the high levels of expression of CD20 on B cell lymphoma and leukemia cells, many patients with B cell malignancies are unresponsive to, or become resistant to, treatment with the anti-CD20 monoclonal antibody rituximab, at least in part due to mechanisms of complement inhibition (Harjunpaa et al., Scand. J. Immunol, 2000 51; 634-641). Therefore, there is a particular need for molecules that are capable of increasing CDC.